We focus on the mechanism of binding of adhesive proteins to their platelet receptors, a key process in the formation of hemostatic plugs, and in the formation of vasooclusive thrombi (coronary, cerebral, and lung microcirculatory thrombosis). The two main aspects of binding of adhesive proteins, namely, the recognition specificity of the glycoprotein IIb-IIIa complex (common platelet receptor for adhesive proteins) and regulation of this receptor from non-binding to binding mode by the platelet agonist, ADP will be studied. To investigate why the unique receptor recognition domain on the human fibrinogen gamma chain is iso-specific with the ubiquitous RGD domains in the alpha chain in regard to their interaction with GPIIb-IIIa, we will use covalent labeling with peptide probes. The GPIIb-IIIa interaction with other adhesive proteins (vWF and fibronectin) will be similarly examined. The topography of "contact sites" on fibrinogen and GPIIb-IIIa decorated with specific antipeptide Fab antibody fragments in electron microscopy will be determined. 2D electron microscopic crystal- lographic analysis of GPIIb-IIIa and 2D H-1 NMR spectroscopic analysis of synthetic peptide analogs of fibrinogen and GPIIb-IIIa will help to develop a molecular model of the fibrinogen-platelet GPIIb-IIIa interaction. Regu- lation of the GPIIb-IIIa complex in platelets stimulated with ADP, will be studied with emphasis on the structure/function of the ADP receptor and protein kinase C species. We will clone cDNA for the ADP receptor and study its expression. We will identify the species of protein kinase C in platelets. We will delineate the role of diverse species of protein kinase C in phosphorylation of GPIIIa and ascertain whether this linkage is direct or involves phosphorylation of an intermediate protein. The results of these fundamental approaches to platelet adhesive receptors will provide useful information for the design of novel inhibitors of platelets.